Substance abuse is one of the nation's leading health issues, leading to more illnesses, disabilities, and deaths than any other modifiable health condition. Substance use among adolescents and young adults is of particular concern, as rates in youth are higher than among any other age group and because early use is associated with a higher risk of later abuse and dependence and a higher incidence of related risk-taking behavior. Thus, a better understanding of the causes of substance use is a central issue. The primary goal of this study is to examine genetic and environmental predictors of youth substance use. This study will expand upon extant research by being the first to utilize an aggregate genetic risk score (AGRS) approach to study substance use behaviors, by incorporating cumulative measures of environmental risk and promotive factors, and by examining GxE effects and gender differences in substance use predictors, thus allowing for a more comprehensive assessment of environmental and genetic influences than has been done in the past. The following specific aims will be addressed: Specific Aim 1: To examine the direct, independent effects of: (a) individual biologically- and empirically-supported genetic risk polymorphisms in the dopaminergic system (measured in the DRD2, DRD4, DAT1, and MAO-A genes);(b) cumulative environmental risk;and (c) cumulative environmental promotive factors on youth alcohol and drug use. Specific Aim 2: To examine the cumulative effect of aggregate genetic risk on youth substance use. Specific Aim 3: To examine how aggregate genetic risk interacts with cumulative environmental risk and promotive factors to predict youth substance use. Specific Aim 4: To test for gender differences in the association between youth substance use and cumulative genetic and environmental predictors. Data will be drawn from a national longitudinal sample of 2,352 youth who participated in surveys and DNA sampling in the National Longitudinal Study of Adolescent Health, with individuals followed from early- to mid- adolescence (ages 12-18) into early adulthood (ages 18-26). Regression analyses will examine main and interactive effects of cumulative environmental risk and promotive factors and aggregate genetic risk on youth alcohol and drug use and will test for gender differences in substance use predictors. Results will provide a better understanding of the etiology of youth substance use and will provide evidence of the utility of AGRS methods for studying genetic influences on substance use. Further, findings will add to what is still a rather sparse and contradictory literature on genetic effects on substance use and will help shed light on discrepant findings regarding gender differences in substance use etiology. PUBLIC HEALTH RELEVANCE: Substance abuse poses serious physical and mental health risks, causing more deaths, illnesses, and disabilities than any other modifiable health condition, and affecting adolescents and young adults at rates that are much higher than rates among other age groups. In order to better prevent the negative health consequences associated with substance abuse, it is imperative to understand the factors that contribute to the development of substance use problems in adolescents and young adults. This project aims to utilize cumulative models of genetic and environmental risk and protective factors to examine the independent and interactive effects of genes and environmental contexts on substance use in a national longitudinal sample of youth in the U.S. and to examine gender differences in predictors of substance use behaviors.